Figure 6. Combination of CDK4/6 and MEK inhibitors induces greater inhibition of phosphorylation of S6 and other growth factor signaling and cell cycle proteins in vivo in PDX models of KRAS mutant CRC.

(A), Protein lysates were obtained from tumors after 21 days of treatment with vehicle control (C), trametinib (MEK), palbociclib (PD), or trametinib + palbociclib (MEK/PD), and RPPA was performed. Protein levels were normalized to the geometric mean of vehicle-treated controls, and a heatmap of the most differentially expressed proteins was generated. Values are log2-transformed fold-change compared to the geometric mean of the controls. (B), Median expression levels of selected proteins in KRAS mutant CRC PDXs treated with trametinib (MEK) alone, palbociclib (PD) alone, or the combination (MEK/PD) for 21 days, relative to vehicle-treated control. p-values were determined using paired Student's t-test. (C), Percentage of nuclear area stained by Ki67 antibody. Data represent mean ± SD of samples from 3–4 mice. *p ≤ 0.02, ♦p < 0.003 by Student's t-test. (D), Representative immunohistochemistry images for Ki67 staining.